Mesenchymal stem cell-like properties of CD133+ glioblastoma initiating cells

Abstract

// Lorena Favaro Pavon 1, 2 , Tatiana Tais Sibov 1 , Daniela Mara de Oliveira 3 , Luciana C. Marti 2, 4 , Francisco Romero Cabral 2, 5 , Jean Gabriel de Souza 6 , Pamela Boufleur 6 , Suzana M.F. Malheiros 1, 7 , Manuel A. de Paiva Neto 1 , Edgard Ferreira da Cruz 8 , Ana Marisa Chudzinski-Tavassi 6 , Sérgio Cavalheiro 1 1 Department of Neurology and Neurosurgery, Escola Paulista de Medicina-Universidade Federal de São Paulo (EPM-UNIFESP), São Paulo, Brazil 2 Hospital Israelita Albert Einstein (HIAE), Experimental Research, São Paulo, Brazil 3 Department of Genetics and Morphology, Universidade de Brasília, Brasília, Brazil 4 Allergy and Immunopathology Graduate Program, Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brazil 5 Faculdade de Ciências Médicas da São Casa de São Paulo, São Paulo, Brazil 6 Biochemistry and Biophysics Laboratory, Butantan Institute, Neuro-Oncology Program, São Paulo, Brazil 7 Hospital Israelita Albert Einstein (HIAE), Neuro-Oncology Program, São Paulo, Brazil 8 Discipline of Nephrology, Escola Paulista de Medicina-Universidade Federal de São Paulo (EPM-UNIFESP), São Paulo, Brazil Correspondence to: Lorena Favaro Pavon, email: l.pavon@unifesp.br ; lorenap20111@hotmail.com Keywords: neurospheres, CD133 + , MSC immunophenotype, TEM, tumorigenesis in vivo Received: February 03, 2016      Accepted: April 16, 2016      Published: May 27, 2016 ABSTRACT Glioblastoma is composed of dividing tumor cells, stromal cells and tumor initiating CD133 + cells. Recent reports have discussed the origin of the glioblastoma CD133 + cells and their function in the tumor microenvironment. The present work sought to investigate the multipotent and mesenchymal properties of primary highly purified human CD133 + glioblastoma-initiating cells. To accomplish this aim, we used the following approaches: i) generation of tumor subspheres of CD133 + selected cells from primary cell cultures of glioblastoma; ii) analysis of the expression of pluripotency stem cell markers and mesenchymal stem cell (MSC) markers in the CD133 + glioblastoma-initiating cells; iii) side-by-side ultrastructural characterization of the CD133 + glioblastoma cells, MSC and CD133+ hematopoietic stem cells isolated from human umbilical cord blood (UCB); iv) assessment of adipogenic differentiation of CD133 + glioblastoma cells to test their MSC-like in vitro differentiation ability; and v) use of an orthotopic glioblastoma xenograft model in the absence of immune suppression. We found that the CD133 + glioblastoma cells expressed both the pluripotency stem cell markers (Nanog, Mush-1 and SSEA-3) and MSC markers. In addition, the CD133 + cells were able to differentiate into adipocyte-like cells. Transmission electron microscopy (TEM) demonstrated that the CD133 + glioblastoma-initiating cells had ultrastructural features similar to those of undifferentiated MSCs. In addition, when administered in vivo to non-immunocompromised animals, the CD133 + cells were also able to mimic the phenotype of the original patient’s tumor. In summary, we showed that the CD133 + glioblastoma cells express molecular signatures of MSCs, neural stem cells and pluripotent stem cells, thus possibly enabling differentiation into both neural and mesodermal cell types.